Methods and Compositions for Treatment of Dermal Conditions

ABSTRACT

The present invention comprises methods and compositions for the treatment of pathological conditions of the dermis and dermal structures of animals and humans. In particular, the present invention comprises the use of topical delivery vehicles, including hydrogels, which incorporate active agents such as organic acids, for the treatment of dermal conditions.

PRIOR RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 10/207,936, filed Jul. 29, 2002, which isincorporated herein in its entirety.

FIELD OF THE INVENTION

This invention discloses methods and compositions for the treatment ofdermal conditions. Particularly, this invention relates to treatment ofpathological dermal conditions using a variety of topical deliveryvehicles to provide active agents to the site or sites of pathology.

BACKGROUND OF THE INVENTION

The dermal structures of humans and other animals are often the site ofinfections or attachments by other living organisms. Dermal structuresinclude, but are not limited to, skin, hair, hair follicles, cornea,sclera, organ linings, pleural coverings, dura, toenails, fingernails,hooves, horns, mucous membranes, and other cellular structures made fromepithelial cells or keratinized structures. Organisms that live in or onthe dermis or dermal structures of humans and animals includemicroorganisms such as yeasts, fungi, bacteria, viruses, mycoplasma, andinsects such as dust mites, ticks, lice and other arthropods.

The presence of these organisms in and on dermal structures often causea range of changes, from merely unsightly to pathological conditions, tothe dermis and dermal structures, and can interfere with the functionsof the dermis and dermal structures of the host organism. Additionally,the presence of these organisms can result in immunological responses bythe host and cause secondary problems at the site or a general responsethroughout the entire host organism. Thus, there is a need to preventinfection or attachment by such organisms, control the amount ofinfection or attachment by such organisms, treat the affected sites, andprevent the re-infection and re-attachment by such organisms from theenvironment.

One of the most common and difficult to treat dermal conditions isinfection of nail structures. The finger and toenails of humans arespecialized tissue structures that are closely related to claw and hooftissues in animals. The nails constitute an important protectivestructure at the distal ends of the fingers and toes that shield thehighly sensitive extremities from triggering pain or sensation oncontact with the external environment. Nails also function as animportant tool that is used to increase the range of dexterousaccomplishments. Humans have developed great pride in the function andappearance of nails. In many cultures, painting and decoration of thenails of both the hands and feet are common place.

Nails, like most anatomical structures of the body, are susceptible todisease processes. One of the pathological conditions that is common forhumans is caused by microbial invasion of the nail or surroundingtissues. Although the condition is not life threatening, infection ofthese tissues can compromise the appearance and the function of theaffected nail. One such condition results from the invasion of thetissues by one or more of several fungi. Fungal involvement in nailinfection has been termed onychomycosis.

Onychomycosis, or fungal infection of the nail, is the most common causeof nail dystrophy. The incidence of the condition has been difficult todetermine largely because it is not life threatening and rarely isreported. It has been estimated that the incidence ranges from 3% to 23%of the total population in western cultures. There is no clearunderstanding of the circumstances that predispose to this condition. Ithas been suggested that there is a relationship between trauma to thenail region and the occurrence of infection. However no studies haveconfirmed this hypothesis.

It is known that certain lifestyle and climatic situations seem tocontribute to onychomycosis. One example is the greater than 80%occurrence rate of onychomycosis in the general population in outlyingnortheastern areas of Russia where long cold winters are encountered.This is likely due to the necessity of using heavy protective footwearfor prolonged periods to protect the feet from the cold. This exposesthe foot, and more particularly the nails, to prolonged moist warmconditions that may encourage the growth of the fungi.

In western cultures it is well known that there is an age relateddistribution in the incidence of onychomycosis. The condition is muchmore prevalent in elderly individuals. Indeed it has been estimated that80 to 90% of the elderly in the U.S. and Canada have at least one ormore of their nails involved. One reason for the increase with age isthat onychomycosis poorly responds to treatment, hence is seldom treatedso there is an accumulation of cases. Other factors that may contributeto the increase with age are a general waning of innate and specificimmunity to fungal pathogens as well as an increased accumulation ofco-morbidities that may contribute to invasion by the fungal pathogensassociated with onychomycosis.

Onychomycosis is a dystrophic condition of the nails of the feet andhands. Fungal infection of the nails results in characteristic changesin the appearance to the structure. The appearance is often used todescribe the degree of severity of the infection. Clinicians often useappearance alone in differential diagnosis of the condition. Knowledgeof the state of the disease is often useful in determining the course oftreatment and the likelihood of success in the management of thedisorder. The common forms of the disease are listed in Table 1.

TABLE 1 State of disease Tissue involve Severity Distal Lateral Fungalinvasion at the Superficial Subungual extreme distal end ofOnychomycosis the nail bed. (DLSO) Proximal Fungal invasion at theSuperficial to severe. Subungual proximal end of the nail bed. Mostoften in Onychomycosis immunocompromised (PSO) people. White SuperficialNail plate only resulting in Superficial to severe. Onychomycosisdiscrete to extensive white (WSO) patches or streaks in the nail. TotalDystrophic Entire nail bed involved. Severe. Onychomycosis (TDO) EndonyxPartial or complete Superficial to severe. involvement of nail plate.

These different presentations are important in predicting the outcome ofa treatment strategy. The anatomy of the nail and its supportingstructures profoundly influence the effectiveness of treating thetissues to rid them of the fungal pathogens. The reason for this is thatnail structure and anatomy are complex and, to some degree, are isolatedfrom systemic circulation. Furthermore the nail plate is relativelyimpermeable to penetration by topical agents.

The anatomy of the human nail is important for the understanding of theprocess that results in onychomycosis. The nail unit is a form ofspecialized epidermal tissue. The nail apparatus, which comprises allthe elements colloquially referred to as “the nail”, is composed ofdistinct structural elements. The most prominent structure of the nailapparatus is referred to as the nail plate which is a thin hard flexiblestructure that emerges from skin folds at the extremities of the digits.The nail plate is produced by the nail matrix situated in the proximalfold. The matrix causes nail plate elongation through proliferation ofits epidermal-like cells. The lateral folds hold the nail plate in anorientation so that elongation proceeds towards the distal end of theextremity. The nail plate grows at the rate of 1 mm (toe nail) to 3 mm(fingernail) per month. The nail plate is translucent in appearance,almost always convex in shape and approximately 0.2-0.6 mm thick. It iscomposed of approximately 25 layers of dead, keratinized cells thatoriginate from the matrix. These dead cells are held tightly together byintercellular linkages resulting in a coalescent dense hard plate with asmooth dorsal surface. The ventral side of the nail plate is relativelyirregular which facilitates attachment of collagen fibers which serve toanchor the nail plate to the nail bed. Nail plate elongation continuestoward the distal end of the digit where it parts from the nail bed at apoint termed the hyponychium.

The nail plate, chemically, is largely protein along with approximately10-30% aqueous moisture. Moisture content in the nail plate is directlyproportional to the moisture content of the environment. Immersion inwater will increase moisture content as will occlusion of the surface soas to prevent evaporation. The nail plate also contains between 0.1 to1% lipid. There is no central circulation or lymphatic drainageassociated with the nail apparatus. However the tissues proximal andlateral, and those beneath the nail bed are highly vascularized.Notwithstanding, the matrix is the only viable component of the nail andis the only structure supported by systemic circulation. The remainderof the nail apparatus is non-viable and is separated from systemicsupport by a layer of collagen fibrils and nail plate substrate.

Under normal circumstances the nail plate and hyponychium present aformidable barrier to microbial penetration. Indeed, most cases to ofonychomycosis originate in the distal area of the nail which implies adisturbance to the tight junction at the hyponychium. This probablyprovides fungi access to the region beneath the nail plate that is richin organic substrate sufficient to support the growth of the fungi. Lessfrequent, is the direct fungal penetration into the nail plate.Trychopyton mentagrophytes can invade in this way because it producesenzymes that are capable of degrading the protein matrix of the nailplate, thereby enabling the fungus to penetrate directly into thesubstrate. In either case the fungi enter a privileged region that islargely devoid of natural resistance mediated by the immune system sincethere is no systemic circulation to the tissues. Moreover, the absenceof circulation also restricts the ability of delivering systemicanti-microbial agents effectively to the specific sites where the fungiinhabit.

Onychomycosis is an active disease process that involves the growth andreplication of saprophytic fungi in the nail apparatus. Most often thefungi are in the non-viable region between the nail plate and the nailbed. Accurate diagnosis of the condition requires the microscopicexamination and culturing of specimen material taken from the affectedregion. Typically scrapings from the site of infection are firstdigested in a strong solution of KOH, mounted on microscope slides witha suitable stain specific for fungal mycelium, and then visualized fortypical structures common to dermatophytes. In addition, differentialdiagnosis is greatly enhanced by propagation and identification of fungiusing in vitro culturing methods. However, microscopic examination andin vitro culture are time consuming and expensive. Therefore manyclinicians will make an imperical diagnosis based on the appearance ofthe affected nails, lifestyle factors, and age of the individual. Thisapproach may lead to a misdiagnosis of cases resulting in inappropriateand dangerous treatment modalities. There is need for a treatment thatis safe and economical that can be implemented with little or no riskshould the original diagnosis be incorrect.

The current systemic and the topical methods for the management ofonychomycosis are expensive, have low success rates and in many casesexpose the user to considerable risk of central organ damage. This ispredominately due to the need to deliver sufficient active agent to theindividual to achieve an inhibitory concentration in the non-viableregions where the fungi resides. In most cases delivery and accumulationof the active agent is dependent upon diffusion through non-viable andnon-vascularized substrate (nail plate, or anchor protein zone of thenail bed). This often has meant persistent administration of the agentwith its concomitant risk of systemic toxicity.

The alternative to a direct attack on the fungi is the removal of itsprivileged habitat. This can be accomplished by removal of the nailplate which provides both nutrient substrate and protection to thefungal parasite. Surgical ablation is still recommended by some asquicker, and better accepted than chemical ablation which is essentiallypainless. Others condemn it and say chemical ablation is the only way itshould be done. Chemical ablation is done by covering the skin aroundthe nail for protection and then applying 40% urea to the nail. Anocclusive dressing is then put on and left for a week at which time thepatient returns to the doctor for removal. The expense includes aminimum of two doctor visits plus the “procedure” cost. It is effectiveat removing the nail but it is known to have a fairly high failure rateunless combined with drug treatment. Furthermore it requires between 6months to a year for the complete outgrowth of new nail plate and areturn to a normal appearance of the nail apparatus. It is also somewhatcontroversial as to its effectiveness as there are no studies showingactual incidence of cure.

The use of oral drugs has lead to the achievement of excellentpenetration and accumulation of active agents within the nail afterprolonged (months) duration of drug administration. Topicaladministration has also resulted in good penetration and accumulation ofthe active. Drug levels have been recorded by direct assay for theactive agents, yet in both topical and oral administration there hasbeen a dismal record of cure rate. Complicating evaluation of true curerate is that “cure” has been ill-defined. In some studies it is taken tomean the achievement of a normal looking nail apparatus whereas in othercases it is taken to mean the elimination of microscopic or culturedetectable fungi in specimens collected from the treatment site.Regardless of the method of assessment there is clear recognition thatthe high cost of treatment, the poor level of outcome, and theconcomitant risk of side effects from the therapy have identified thatthere is a need for a safe, effective, and economic treatment modalityfor onychomycosis.

There is also a need for treatments for other dermal conditions that areeasily used and applied by patients because the treatment times areoften long and extended. An ideal treatment modality for onychomycosisand other dermal pathologies would be effective and sufficientlystraightforward so that it encourages a high degree of patientcompliance. A simple and relatively short duration of administration ofan agent targeted for the organism responsible for the pathology shouldbe highly effective at controlling or eliminating the disease-state.Effective topical treatment of the conditions requires successfulpenetration of the active agent through the nail plate or dermal layersto the zone most commonly harboring the organism. An effective treatmentwould include the penetration and accumulation/maintenance of aneffective concentration of active agent in the growth site and habitatof the unwanted organism.

Compositions are needed that are effective for treatment of unwantedorganisms causing pathological conditions in the skin and dermalstructures. Such compositions can be used in methods for preventinginfection or attachment, treating existing conditions, and preventingre-infection or re-attachment of organisms in the environment. Suchcompositions should be well tolerated by the patients.

DESCRIPTION OF THE INVENTION

The present invention is directed to methods and compositions for thetreatment of dermal conditions. The compositions comprise topicaldelivery vehicles such as solid matrices, hydrogels, creams, gels andother solutions comprising one or more active agents in effectiveamounts to treat skin disorders and conditions. Methods of the presentinvention comprise application of the compositions to affected areas ofskin or dermal structures so that the one or more active agents aredelivered in an amount effective to treat altered dermal areas orprevent infection or attachment of organisms to a skin area or dermalstructure.

As used herein, skin, dermal or dermal structures refers to the elementsof the integumentary system of humans and animals, including organ andcavity linings, such as pleura, dura, and pericardium, and mucousmembranes and such terms are herein used interchangeably. Theintegumentary system as it is commonly understood by those skilled inthe art refers to the skin, including the epidermis and dermis, whichcomprise layers including stratum basale, stratum spinosum, stratumgranulosum, stratum Iucidum, stratum corneum, papillary layer andreticular layer. Cells which are found in these dermal structuresinclude, but are not limited to, keratinocytes, fibroblasts,melanocytes, dendritic cells, Landerhans' cells, epithelial cells, andMerkel cells. Dermal structures include appendages such as hair,sebaceous glands, sweat glands, follicles, nerve structures, horns,hooves and nails.

One embodiment of the invention comprises compositions and methods fortreating fungal mediated nail infections referred to as onychomycosis. Acomposition comprises a matrix material that comprises one or moretherapeutic agents, latent moisture, one or more humectants, and mayfurther comprise means to secure the matrix in direct contact with anail plate.

Though not wishing to be bound by any particular theory, it is thoughtthat a delivery vehicle such as a polymerized matrix structure wouldprovide a reservoir comprising one or more active agents, water and ahumectant composition that will be delivered to the nail plate whensecured to the nail. The moisture and humectant that are transferred onapplication to the nail will hydrate the nail plate and form a diffusiongradient for the effective delivery of the active agent to thenon-viable areas of the nail apparatus.

Dermal structures are infected by or provide a growth site for a varietyof organisms and the methods of the present invention comprise treatmentof dermal structures affected by such organisms. Such organisms includeorganisms that live in or on the epidermis, dermis or dermal structuresof humans and animals including, but not limited to microorganisms suchas yeasts, fungi, bacteria, viruses, mycoplasma, and insects such asdust mites, ticks, lice and other arthropods.

Organisms termed fungi include a diverse group of free living organismsthat include molds, smuts, mushrooms, mildews and yeast. Collectivelythese organisms are referred to as heterophils, meaning that theyutilize non-living complex organic substances as their source ofnutrients. These organisms play an important role in the recycling ofdead and decaying organic matter in nature. A few fungi have adapted toa saprophytic relationship with higher organisms such as man. Even fewerof these are capable of invading to establish in the unique ecologicalzone of the nails of mammals. Although a diverse number of fungi havebeen described in association with nail dystrophy and other dermalpathologies, the vast majority of cases in the U.S. and Canada arecaused by a group of fungi known as dermatophytes. Dermatophytes haveone property in common; that being that they all are capable of invadingand establishing residence in the tissues associated with the skin.Often fungal infection of the skin is referred to as ringworm and thephrase “ringworm of the nails” has been used to describeonychomycosisis. The principle nutrient source for dermatophytes in skinand nails is keratinized proteins. Keratin is non-viable matrix proteincomplexes derived from epidermal tissues. Typically dermatophytes do notinvade beyond the non-viable keratinized layers. Although dermatophytesconstitute 90-96% of the cases of onychomycosis, other fungi such asyeasts and molds have also been found in association with the disease.

The predominate isolates from infected nails has been Trychophytonrubrum followed thereafter by Trychophyton mentagrophytes,Epidermophyton sp. and Microsporum sp. Non-dermatophyte molds that areoccasionally isolated include Aspergillus niger and Scopulariopsisbrevicaulis. Collectively these less frequently encountered fungiaccount for less than 4-5% of cases. Even less frequently encounteredare yeast. The most common yeast isolate is Candida albicans whichaccounts for 3-4% of the total cases. Interestingly, the C. albicansonychomycosis is more frequent in women than in men, most oftenaffecting their fingernails.

The cell wall of fungi is primarily chitin, a natural long chainpolysaccharide composed largely of poly-(N-acetyl glucosamine). Chitinis extensively distributed in nature, making up the predominatecomponent of the exoskeletons of crabs, spiders and many othercreatures. The cell membranes of fungi are similar to the cell membranestructure of human cells except that fungal cell membranes containergosterol and zymosterol unlike the cholesterol found in mammalian cellmembranes. This is an important difference that has allowed thetargeting of specific anti-fungal treatments. All current anti-fungalagents are based on disrupting the biosynthesis of these sterols.

The biosynthesis of squalene to ergosterol is depicted as:Squalene→Squalene epoxide→Lanosterol→14 DimethylLanosterol→Zymosterol→Fecosterol→Episterol→Ergosterol.

There are several anti-fungal compounds that have been extensivelyevaluated for their activities against fungi and in particular, thedermatophytes which are associated with onychomycosis. TERBENAFINE is anallylamine which blocks the conversion of squalene to squalene epoxide.This results in the accumulation of squalene in the cell. Squalene is animportant intermediary compound in ergosterol synthesis but in higherconcentrations becomes toxic for the fungi as it accumulates inside thecytoplasm. Lamisil® is the trade name for terbinafine and is consideredthe most effective oral medication for onychomycosis. It has anadvantage over others in that it is also the least likely to causeserious side effects following prolonged usage. Its basis foreffectiveness is that it is fungicidal whereas the other agents arefungistatic. TERBINAFINE is less effective for yeast and to some extentmolds. It persists for several months after treatment and can bedetected in the nail bed at one week. Clinical cure rate is 37% of casesof the total dystrophic onychomycosis (TDO) form of infection. Seriousside effects include liver damage and severe generalized skin reactionssuch as the Stevens-Johnson's syndrome requiring hospitalization. Whileserious side effects are not common, there were 11 deaths and 2 livertransplants reported to the US government by 2001 out of 16 cases ofliver failure. At a 37% cure rate for TDO of the great toe and typicallysix months treatment required, the overall cost per cure is around$6,500.

Azol antifungals such as ketoconazole, itraconazole, and fluconazole allblock the conversion of the intermediate, lanosterol to 14-dimethyllanokerol. This process starves the cell of intermediates for thesynthesis of ergosterol. SPORANOX is the trade name for itraconazolwhich has been used for the treatment of onychomycosis. It has beengenerally shown to be less effective than TERBINAFINE in most studies,both in rate of cure and in the relapse rate. It is commonly given as a“pulse”, i.e., one week on and three weeks off the oral medication. Itis more effective than TERBINAFINE against molds and probably againstyeast forms but less effective against dermatophytes. Clinical cure ratewith TDO is about 27%. There is a probable association of pulmonaryedema with SPORANOX with 58 cases as of 2001 including 13 deathsreported. There were 24 cases of liver failure with 11 deaths fromSPORANOX reported to the FDA through 2001. If given daily, the cost isthe same as LAMISIL at about $10/tablet or capsule. The cost is less if“pulse treatment” is used. SPORANOX requires regular liver enzymefunction monitoring to provide early detection of hepatic injury due tothe therapy as is the case for LAMISIL. DIFLUCAN (fluconazole) commonlyused for vaginitis is particularly effective against yeast forms(Candida). It persists in the nail plate for several months aftertreatment. The cure rate for total dystrophic onychomycosis (TDO) isabout 38%. It, like LAMISIL and SPORANOX, is also approximately $10/pilland is a once per day dose but can be used with “pulse treatment” likeitraconazole. Ketoconazole and Griseofulvin are no longer recommendedfor onychomycosis.

Amorolfine blocks conversion of intermediates at two sites in thesynthetic pathway. It blocks both at the conversion of 14-dimethyllanosterol to zymosterol and at the conversion of fecosterol toepisterol. Again this has the effect of limiting cell membrane synthesisand leads to the selective killing of the fungi dependent upon thispathway. LOCERYL is an amorolfine that is used topically as a 5%solution and is approved for use in Europe for treatment ofonychomycosis. It is indicated for mild onychomycosis with no matrixinvolvement and is effective in about 40% of the cases.

PENLAC (ciclopirox olamine) is the only FDA approved topical treatmentfor onychomycosis. It is a topical anti-fungal that is painted on thenail, typically once or twice a day for a year or more. It has beenrecommended for use in combination therapy involving topical plus oralapplication. In vitro, it is fungicidal against dermatophytes, yeast andmolds that typically cause onychomycosis. In a study of mild to moderatedistal lateral subungual onychomycosis (DLSO) form of the disease (anaverage of 40% of nail involved and no matrix infection), it had a 7%cure rate. At $420 per treatment for the drug cost, coupled with a 7%cure rate, extrapolates a cost per cure of almost $8,500 presuming threeoffice visits per patient.

Many individuals with nail dystrophic conditions have turned toalternative concoctions in search of a cure. Tea tree oil (Melaleucaalternafolia) has been claimed to be effective as a “natural” treatment.The only clinical study available is one using it as the “control”.There were no cures in the control group of that study. Otheralternative treatments advertised include Varisi (50% citrus seedextract, 25% ascorbic acid and 25% glycerin) and Nonyx Gel (acetic acid9.75%) topically applied daily. Again there is little controlledclinical study information available for either of these and theylogically would be unlikely to be effective.

Anti-fungal agents are specifically targeted to interfere with metabolicfunction of fungi and this can be repeatedly demonstrated underlaboratory conditions. However known agents delivered either topicallyor systemically or, in some cases, as a combination have a low successrate. In theory, these drugs should have a cure rate that approaches100% success. Some of the factors contributing to the low success rateare:

-   -   1. Nail matrix involvement in the condition where it is        difficult to penetrate and deliver topical agents at effective        concentrations.    -   2. Penetration of the anti-fungal into the areas were it can be        active in controlling fungal growth is problematic. The lateral        borders of the nail are exceptionally difficult regions to cause        the accumulation of effective levels of actives regardless of        whether oral agents or topical agents are used.

Presence of a dermatophytoma, a thick mass of keratin debris between thenail plate and bed, which contributes to poor penetration of either oralor topical drugs into the nail apparatus.

-   -   3. Progression of the dystrophic condition to a state known as        oncholysis whereby the nail plate detaches from the nail bed        resulting in poor penetration and accumulation of oral or        topical drugs.    -   4. There are at least 21 variants of T. rubrum which is the        predominant causative parasite of onychomycosis. It is possible        that some may be more resistant to some treatments.    -   5. Fungal arthrospores are a dormant state of the fungi and are        relatively resistant to anti-fungal agents.    -   6. An individual's compliance to a treatment regime is        singularly difficult to maintain and is likely a major        contributor to poor success rates with all current modalities.        AU current treatments require long periods with (usually) daily        intervention to accomplish resolution of the infection. One        survey showed a 48% incidence of a failure to adhere to the        treatment schedule and 25% of individuals stopped completely        before the end of scheduled therapy, often because they thought        they were cured and didn't need it any more even though they        did.    -   7. Ineffective elimination of fungi from vectors such as        footwear, flooring and bathing surface, and keratinized skin        layers results in continuous recurrent introduction to of the        fungi.

The nail apparatus presents unique challenges. Penetration of activesubstances, regardless of whether it is from systemic or topicalapplication is dependent upon the movement of the agent throughnon-viable tissues where the fungi reside. It is likely that the mosteffective method of distribution through this type of environment wouldbe through diffusion. Moisture or lipid provide the only fluid phasecomponents in the nail apparatus that can support diffusive distributionof the agent. Unfortunately neither of these fluid phase components isin abundant concentrations within the nail plate and nail bed substratesto be exploited for effective delivery of actives. Furthermore thetypical infected nail plate is usually considerably thickened inresponse to fungal activity and therefore presents a greater barrier todiffusion through the small amount of normal latent moisture in thenail.

Fortunately the nail plate is hydrophilic and will readily absorbmoisture into the substrate. Therefore either exposure to moisture or,conversely, the use of agent(s) that attract moisture from thesurrounding environment can substantially increase the moisture contentof the nail plate. This would then provide a diffusion gradient for thetransport of an antifungal agent into the sub-plate matrix to act on thefungi. It is known that penetration of compounds through the nail platecan be considerably enhanced by increasing the moisture content in theplate matrix. Therefore a device that incorporates both the activeagent(s) and a moisture management system in a reservoir fashion wouldrepresent an improvement on previous devices that have been describedfor aiding in the treatment of onychomycosis.

The majority of onychomycosis involves invasion of the fungi into thebed of the nail. The exceptions are associated with some yeast andmolds, and most of the cases secondary to Trychopyton mentagrophytesinvolve the actual nail plate. The invasion of the hard, devitalizedkeratin structure of the nail plate is assisted by enzymatic degradationof the substrate. This capability is most notable in T. mentagrophyteswhich has enzymes that allow it to digest the nail plate which opens atract for the saprophyte to gain access into the deeper regions of thestructure. Other organisms may also follow its course to establish aco-incident infection below the surface. In advanced stages ofonychomycosis both the plate and bed are usually involved. Whilepermanent injury to the bed or matrix will result in permanent loss ofthe nail plate, most fungal infections do not cause permanent damage.With resolution of the infection, a normal nail can usually be restoredby outgrowth of new nail plate structure.

There is a clear differential in the distribution of the disorderbetween toe and finger nails. Toenails are at least four times morecommonly involved than fingernails. One reason may be that the warm,moist environment provided by shoes and stockings is optimal for thegrowth of dermatophytes. Other factors that may contribute to theincreased incidence in toenails is that they are slower growing, areless frequently subjected to cleansing practices, and are continuallyassaulted with fungi that inhabit footwear. This is supported by thefinding that onychomycosis is co-incident with dermatophyte infectionselsewhere on the individual. Approximately a third of people with tineapedis, or athletes' foot will develop onychomycosis.

Adjuvants to attempt enhanced delivery of active agents through the nailplate are not novel. U.S. Pat. Nos. 5,840,283 and 5,972,317 describe theuse of a proteolytic enzyme in conjunction with a medication for thetreatment of nail fungus. Moisture may be another useful agent forfacilitating the movement of active agents through the nail plate.Compositions of the present invention may further comprise a humectantwhich will attract aqueous moisture from the atmosphere as well as thatwhich is transpired normally into the nail plate. An embodiment of ahumectant of the present invention would be of sufficient low molecularsize to penetrate and localize in the nail plate so that moistureattracted to the humectant will also localize in the nail.

Numerous organic compounds and salts act as humectants or waterretention agents. Humectants may include but not necessarily be limitedto any of several organic alcohols such as glycerol, butanol, propanol,isopropyl alcohol, ethanol, methanol, propylene glycol, polyethyleneglycol, ethylene alcohol, and butyl alcohol. In addition, several salts,including but not limited to sodium chloride, lithium chloride, copperchloride, magnesium chloride, magnesium sulfate, mangenese sulphate,aluminum sulfate, zinc sulfate, and zinc chloride may function as waterretention agents to assist in the hydration of the matrix. In thepresent invention, the preferred humectant is an organic alcohol sincethese are well tolerated by tissues yet are of sufficiently smallmolecular size as to readily migrate with the moisture into the nailplate matrix. The most preferred organic alcohol is glycerol, inconcentrations ranging from 4 to 40 percent total weight of thecomposition. Though not wishing to be bound by any particular theory, itis believed that the humectant is helpful to the composition as itserves to both attract and cause the deposition of moisture in thecomposition as well as to preserve the aqueous moisture component toprevent loss by evaporation. It is intended that embodiments of theinvention, when placed and secured to the nail plate, will deliveraqueous moisture into the plate to form the diffusion gradient of theactive agent in the material. Equilibrium of distribution should thenresult in uniform concentration throughout the composition of theinvention and the nail plate. It is also known that increased hydrationof the nail plate increases the permeability of materials of varyingmolecular weights through that substrate. Therefore an added benefit ofthe incorporation of a humectant such as an organic alcohol, an examplebeing glycerol, would assist in the penetration of agents of a varietyof molecular sizes through the nail plate.

The present invention comprises compositions comprising a matrix thatwill provide molecular space for the incorporation of one or more activeagents along with the moisture and one or more humectants duringproduction of the product. Moreover, the composition of the materialshould be suitable for delivering the material from the matrix to thenail plate upon application during treatment. A suitable component wouldbe any component that is composed of a flexible material that willconform to the contours of the nail. The material also should be capableof containing an effective amount of aqueous moisture to form adiffusion gradient between the matrix and the site of application, whenapplied, as well as comprise the other components of the delivery systemuntil they function during the application.

Numerous substrates may be suitable for matrices. These include naturaland synthetic hydrophilic polymers that may include, but are not limitedto, rubber, collagen, animal hide, hyaluronic acid, dextran, alginates,cellulose, carboxymethycellulose, hydroxymethycellulose, elastomers,polyethylenes, polypropylenes, polybutyrate, polyacrylate,polyacrylamide, polybuterate, polyurethane foam, silicone elastomer,nylon, vinyl or cross linked dextran. If cross-linked dextran is used,it is preferred that the molecular weight of the dextran polymer isbetween 50,000 and 500,000. The polymeric structure of the scaffoldingof the invention may either be of a cross-linked or non-cross linkedpolymer. A preferred embodiment is composed of a cross-linked polymer ofthe polyacrylate family of polymers. A most preferred embodiment iscross linked polyacrylamide. as it possesses carrying capacity formoisture, active agents and humectant and is non-degradable so that itwill persist through the application and treatment phase. An example ofsuch a polyacrylamide matrix is taught by U.S. Pat. No. 5,196,190 toNangia, et al., which is herein incorporated in its entirety.

Another component of the embodiments of the present invention is a novelanti-fungal agent. It is intended that an embodiment of the presentinvention is used for the delivery of one or more of the known orcontemplated anti-fungal agents, provided that the one or more agentsare capable of distribution via diffusion in an aqueous gradient. Inaddition to known therapeutic anti-fungal compounds, it is known thatmany other substances are capable of inhibiting or killingdermatophytes. In certain in vitro culture methods, it has been foundthat increasing the acidity is useful in controlling the growth ofdermatophyte fungi. Low pH (i.e., high hydrogen ion concentration)prevents the growth of dermatophytes which are the principle group offungi responsible for onychomycosis. The present invention comprisescompositions comprising one or more acidic agents that are capable ofincreasing the hydrogen ion concentration of the medium. A preferredsource of acidity in the composition is a weak organic acid.

In the present invention it is contemplated that weak organic acids canachieve relatively low pH values in aqueous gradients yet are welltolerated when in contact with tissues. There are numerous suitableorganic acids, including but not limited to, citric acid, sorbic acid,ascorbic acid, salicilic acid, tannic acid, succinic acid, lactic acid,pyruvic acid, alpha ketoglutaric acid, glutamic acid, acetic acid andbutaric acid. Salicylic acid has both keratinolytic properties as wellas being a proton donor. Other anti-mycotic active agents include,iodine, DMSO, azole derivatives, undecylenic acid, tea tree oil, andurea.

A preferred embodiment of the composition comprises at least one activeagent, wherein at least one active agent is citric acid. Citric acid isa preferred organic acid because it has 3 carboxyl residues which havedistinct pK values for dissociation of protons into the aqueousenvironment. Therefore the buffered pH can be maintained at a relativelylow level through out the application period. Furthermore, citric acidis generally regarded as safe.

A preferred embodiment comprises sufficient citric acid to achieve andmaintain a concentration between 0.1-10% w/w citric acid in thenon-viable portions of the nail apparatus after equilibration of thediffusion gradient established by the moisture delivered by the matricesof the present invention. Ideally the matrix would contain betweenapproximately 1 and 20% citric acid to accomplish this. More preferablythe matrices would possess a concentration between 5 and 15 percent withthe most preferred embodiment having between 7 and 13 percent citricacid incorporated in the matrix.

An additional component of embodiments of compositions of the presentinvention is a moisture management system that is integral to thematrices. The moisture management system may include substances thatattract and hold moisture in the matrix. Mucopolysaccharides interactwith moisture, which results in hydration of their polymeric structure.Water is often referred to as being “bound” to the polysaccharide. Thisloose binding of water serves to enable mucopolysaccharides to provide areservoir effect so that water can be incorporated until another driersubstance can take it away. Many polysaccharides may play this role butuseful ones for the purpose of the invention would be those that do notgel when exposed to excess water. Numerous polysaccharides may serve thefunctional purpose of the mucopolysaccharide in the present inventionincluding but not limited to acacia, distarch adipate, alginic acid,agar, arabinogalactan, carrageenan, locust bean gum, methylcellulose,eucheuma seaweed, xanthan gum. One such mucopolysaccharide is derivedfrom the Guar tree and is referred to as guar gum. A range of guar gumbetween approximately 0.01 kg to 100 kg, preferably betweenapproximately 0.1 kg to 10 kg, and most preferably between approximately0.5 kg to 2 kg is generally sufficient. Other non-gellablepolysaccharides and galactomannan macromolecules include but are notlimited to lucerne, fenugreek, honey locust bean gum, white clover beangum and carob locust bean gum. A preferred embodiment of compositions ofthe invention would contain guar gum for the purpose of holding water inthe substrate.

An embodiment of the compositions of the present invention includescompositions that are capable of being affixed to the site of infectionor growth of the unwanted organism, and the compositions are affixed byattachment elements. The utility of the device would be approximatelythe same whether it were simply a matrix with the properties above orwas provided with some securing capability by the attachment elements.An embodiment of the invention is a matrix which is capable of hydratingand acidifying the nail bed and which would be easy to use. Ease of usewould be facilitated if the device had an attachment element of anadhesive backed tape or film that extended beyond the border of thematrix such that the adhesive could be used to wrap the toe or finger soas to secure the device to the affected area. Ideally the attachmentelement would have a relatively low moisture vapor transmission rate soas to aid in the retention of moisture in the matrix and occludemoisture loss due to evaporation. Notwithstanding any pattern that aidsin application would be a desirable feature of the device. It is furthercontemplated that an attachment element also includes the use of anadhesive applied to the surface of the contact portion of the matrix sothat the matrix would be securely fixed to the affected area by theadhesive, thereby preventing it from slipping away from the nail. Anadded advantage would be an open pattern adhesive since many adhesivesare hydrophobic and only minimally allow moisture movement through thesubstrate. Such an open pattern adhesive would not interfere with thetransfer of moisture and active agents from the matrix to the affectedarea being treated. The matrix could also comprise an attachment elementof a tacky or adhesive material incorporated in the matrix so that thematerial could be molded to the affected area and would remain attacheddue to its inherent cohesive properties. These examples are not to beseen as limiting, but any attachment element that is capable of securingor maintaining the matrix at the site of application is contemplated bythe present invention and many such attachment elements, for examplethose used for securing bandages, are known to those skilled in the art.

Examples of attachment elements include pressure sensitive adhesivesincluding, but not limited to, polysiloxanes (e.g., polydimethylsiloxanes, polydiphenyl siloxanes, and siloxane blends),polyisobutylenes, polyacrylates, acrylic acid-acrylate copolymers (e.g.,copolymers of acrylic acid copolymers with 2-ethylhexyl acrylate orisooctyl acrylate), and tacky rubbers such as polyisobutene,polybutadiene, polystyrene-isoprene copolymers, polystyrene-butadienecopolymers, and neoprene (polychloroprene).

An attachment element, such as a pressure sensitive adhesive material,with respect to highly hydrated biological tissues, such as mucosaltissue, exhibit good tack when adhered to hydrated biologicalsubstrates. To be bioadhesive, water should provide a plasticizingeffect on the polymer, i.e., the polymer should be hydrophilic. Forexample, the range of typical adhesives includes slightly cross-linkedpolyacrylic and polymethacrylic acids (EP 0371 421) as well as blends ofhydrophilic cellulose derivatives (40-95%) with polyethylene glycol(PEG) (U.S. Pat. No. 4,713,243). Bioadhesives become tacky as the crosslinked polymer swells in significant quantities of water. Such adhesivesare taught in U.S. Pat. No. 6,576,712, which is herein incorporated inits entirety.

In the present invention, it is contemplated that embodiments ofcompositions of the delivery platform would function on contact with thenail plate to deliver aqueous moisture that will increase the hydrationlevel in the nail plate. The organic acid in the material would thenmove from the delivery platform to establish an even distribution ofacidity throughout the device and the nail plate and other non-viabletissues of the nail apparatus.

A device with the above properties comprises a sheet of matrix materialthat could be cut to the size and shape of finger and toe nails. Thematerial is applied directly to the nail with attachment elementsprovided by the tackiness of the polymer of the matrix to hold it inplace and/or by attachment elements such as an adhesive polymer coatingor adhesive backing securing device. Such a device is worn for severaldays, is preferrably transparent which has cosmetic appeal, andmaintains the moisture gradient due to the humectant or water retentionproperty of the material.

Another embodiment of the composition is in the form of an amorphoushydrogel material composed of a plasticizer such as carboxymethylcellulose or hydroxymethyl cellulose in water. Such amorphous gels areapplied directly from the packaging into the application site andsmeared so that they conform to the contours of the area being treated.An advantage of such a material is that it is convenient to apply, issticky so that it localized to the area of application, and may haveadvantage in penetrating the lateral and proximal nail fold areas of thenail during application. Prototypes of an amorphous hydrogel wereprepared so as to contain either 8, 12, or 16% w/w citric acid. Such ahydrogel is made by mixing 10% w/w glycerol into water. The appropriateamount of citric acid (8 to 16%) is then added and dissolved bystirring. 1.5% carboxymethyl cellulose and 0.3% powdered polyacrylamidematrix (for example, the matrix taught by Nangia patent or those taughtin Example 1, except no glycerol or citric acid is added) was blendedinto the water containing citric acid and glycerol to form a viscousgel. The gels are then packed into foil laminate squeeze tubes andsealed using a bar sealer. The amorphous gels were evaluated byapplication of the material to infected toe nails by squeezing outsufficient material to cover the entire nail plate with a layerapproximately 1-2 mm thick. The viscous gel was moderately adhesive tothe nail plate so that it stayed in place regardless of whether coveredwith a dressing, sock or left uncovered. All of the gel samplesadequately hydrated the nail plate sufficiently so as to allowdebridement of the nail over the affected area without difficulty. Thehydrated infected nail lifts from the nail bed and then is cut or pulledaway without pain or discomfort. Subsequent applications of either the 8or the 12% citric acid samples on a daily frequency resulted in there-growth of healthy new nail. Prototypes containing the 16% alsoresulted in new nail growth but occasionally also caused mild irritationin the skin area around the affected nails.

Another embodiment of the compositions of the present invention comprisecreams, salves, emulsions, lotions, pastes, white petrolatumcompositions, or other lotion-type materials that provide one or moreactive agents. Such an embodiment would have a moisturizing effect onthe keratinized layers of skin. It is thought that surrounding skin is apotent reservoir for dermatophytes that are capable of re-infectingnails. Such an embodiment hydrates the keratinized skin and create adiffusion gradient for the delivery of the active such as citric acidinto the non-viable layers where the fungi would inhabit. Suchembodiments are used prophylactically or actively to eliminate fungal orother microbial inhabitants of keratinized skin.

For example, the fungi commonly associated with onychomycosis aredermatophytes. This group of fungi is uniquely adapted to live innon-viable materials such as the keratinized layer of epithelium orhair. Many individuals harbor these fungi unaware of their presence.Under circumstances such as injury, supra-hydration (e.g., sweaty feet),or decrease in natural resistance, these fungi may spread to otherareas. This phenomenon has been used to explain the high recurrence ofinfection of nail bed in individuals who have successfully resolved about of onychomycosis. Incorporation of organic acids, such as citricacid, in an oil and water emulsion provides a convenient deliveryvehicle for application and for creating the moisture diffusion gradientin the skin sufficient to allow the migration of the active, agents intothe non-viable keratinized layers at the application site.

An example of such a composition is an oil emulsion. An oil emulsioncontaining 3% citric acid was made by dissolving citric acid powder in acommercial oil in water emulsion (Eucerin®). The blend was packaged in acosmetic 250 g jar. The emulsion was applied daily to the feet andworked into the skin by rubbing. The material had a cooling and soothingfeeling and caused no adverse effects to the skin. No new infected nailsdeveloped during the time that the cream was used.

Compositions of the present invention can also include shampoos, whereinthe moisture is provided to the scalp and hair follicles or the shampooformulation may be used as a topical cream for application of the activeagents to the skin. Other compositions comprise creams or foams.

Compositions of the present invention comprise one or more activeagents. Such active agents include, but are not limited to, organicacids, and antifungal agents such as selenium sulfide, resorcinol,ketoconazole (NIZORAL) Clotrimazole (such as LOTRIMIN). Terbinafine(LAMISIL), Ciclopirox olamine (LOPROX), Diflucan, anti-yeast compounds,antibacterial compounds, and antiviral compounds. Such compositions areapplied topically to the site of infection or growth of the unwantedorganisms.

Compounds contemplated for use in the present invention include, but arenot limited to, those formulated for topical administration, forexample, as a skin lotion, suntan lotion, cosmetic lotion, moisturizer,lip balm, eye makeup, face cream, and the like. A typical formulationincludes one or more compounds as described herein, in combination withmoisturizers, antioxidants, and the like.

Moisturizers contemplated for use in compositions include, but are notlimited to, occlusive moisturizers, such as, for example, hydrocarbonoils and waxes, petroleum jelly, silicone oils, silicone derivatives,vegetable and animal fats, cocoa butter, mineral oil, fatty acids, fattyalcohols, lanolin, phospholipids, and the like; humectants, such as, forexample, glycerin, honey, lactic acid, sodium lactate, ceramide, urea,propylene glycol, sorbitol, pyrrolidone carboxylic acid, glycolic acid,gelatin, vitamins, proteins, and the like; hydrophilic matrices, suchas, for example, hyaluronic acid, colloidal oatmeal, and the like;essential fatty acids (e.g., Dermasil), elastin, niosomes, and the like.

Antioxidants contemplated for topical formulations include, but are notlimited to, superoxide dismutase, catalase, glutathione peroxidase,glutathione reductase, gamma-tocopherol, alpha-tocopherol, ubiquinol 10,ubiquinone 10, ascorbic acid, uric acid, glutathione, and the like.

Commonly used active ingredients in sunscreen products includepara-aminobenzoic acid (PABA), benzophenone, padimate 0, cinnamates,homosalate, oxybenzone, octylsalicylates, and the like. Exemplarysunscreen products include SHADE SPF15 (available from Schering-PloughCorp., Memphis, Term.), PRE-SUN SPF15 cream (available fromWestwood-Bristol Myers, Buffalo, N.Y.), SUNDOWN SPF15 (available fromProctor and Gamble, Cincinnati, Ohio), BULLFROG SPF36 (available fromChattem, Inc., Chattanooga, Tenn.), DAYLONG 16 (available from SpirigAG,CH-Egerkingen), an emulsion gel containing 70% water, ethanol,phospholipids, carbopol, sorbitol, silicone, amphisol, cetyl alcohol,tocopherol, triethanolarnine, preservatives, and preparations with whitepetroleum jelly as vehicle, and the like.

Commonly used active ingredients in skin care products includealpha-hydroxy acids, tocopherol sorbate, ascorbate, glycolic acid, andthe like.

Three alternative formulations of the topical delivery composition ofthe present invention as described in general terms below. Theseformulations are provided as examples of the present invention and arenot intended to limit the invention in any way.

Formulation 1

Active ingredient, such as citric acid, at preferred percentage

Glycerin 2.0% w/v Propylene Glycol 2.0% w/v Dimethylisosorbide 0.5% w/vEthanol 35.00% v/v Preservatives as needed Water to final volume

Formulation 2

Active ingredient, such as citric acid, at preferred percentage

Glycerin 2.40% w/v Propylene Glycol 0.60% w/v Dioctyl Maleate 1.00% w/vEthanol 28.50% v/v Preservatives as needed Water to final volume

Formulation 3

Active ingredient, such as citric acid, at preferred percentage

Caprylic/Capric Triglyceride 0.25% w/v Propylene Glycol 2.00% w/vDimethylisosorbide 1.00% w/v Ethanol 40.00% w/v Pantothenol 0.25% v/vPreservatives as needed UV A, B and other radiation screens as neededFree radical inhibitors or quenchers as needed Water to final volume

Methods of the present invention comprise treatment of dermal structurescomprising applying a composition of the present invention that iseffective in the prevention of growth or infection of unwanted organismsuntil the growth or infection by the unwanted organisms is lessened orstopped. For example, a method of treating a dermal structurecomprising, a) applying a composition comprising at least one activeagent to a site of a dermal condition, b) maintaining the composition atthe site for a sufficient amount of time so that an effective amount ofthe active agent is delivered. Any of the composition taught herein canfunction in these methods.

Such methods may further comprise treatment of the entire host organismby the concomitant use of oral medications that aid in the prevention orcessation of the growth or infection by the unwanted organisms. Suchoral treatments include antifungal pills. Antifungal pills may be takenjust once (in a single dose) or may be taken once a day for 5 to 10days, or continuously. A short period of time of dosage will mitigateagainst the side effects or risks usually associated with long-term use.Antifungal pills are available include Ketoconazole (NIZORAL),Fluconazole (DIFLUCAN), Griseofulvin and Itraconazole (SPORANOX).

Dermal conditions that are treated by the methods and compositions ofthe present invention include but are not limited to Acne, Grover'sDisease, Pityriasis Lichenoides, Acanthosis Nigricans, Hair Loss(Alopecia Areata), Pityriasis, Rosea, Acrochordons, Hair Loss(Androgenic Alopecia), Pityriasis, Rubra, Pilaris, Actinic Keratosis,Hair Loss (Telogen Effluvium), Plantar Warts, Age Spots, Halo Nevus,Poison Ivy, Allergic Contact Dermatitis, Hand Dermatitis, Poison Oak,Anal Warts, Heat Rash, Pompholyx, Angioma, Herpes Simplex, Pre-cancersof the Skin, Aphthous Ulcers, Herpes Zoster (Shingles), Pruritus Ani(Itchy Butt), Athlete's Foot, Hidradenitis Suppurativa,Pseudofolliculitis Barbae, Atopic Dermatitis, Hives, Psoriasis, AtypicalMoles, Hyperhidrosis, Razor Bumps, Barnacles of Aging, Ichthyosis, RhusAllergy, Basal Cell Carcinoma, Impetigo, Rhyniophyma, Bateman's Purpura,Ingrown Hairs, Ring Worm (Body), Berloque Dermatitis, Irritant vs.Allergic Dermatitis, Ring Worm (Scalp), Boils, Jock Itch, Bruising Backof Arms, Keloids, Scabies, Bullous Pemphigoid, Keratoacanthoma, Scar,Abnormal Candida, Keratosis Pilaris, Schamberg's Disease, Carbuncles andFuruncles, Lentigines (Sun Spots), Scleroderma, Localized CherryAngioma, Lichen Planus, Sebaceous Hyperplasia, Chiggers,Chondrodermatitis Helicis, Lichen Simplex Chronicus, SeborrheicKeratosis, Clark's Nevus, Lichen Sclerosus, Senile Angioma, Cold Sores,Lichen Striatus, Condylomata, Lupus of the Skin, Skin Aging Cysts,Lyme's Disease, Skin Tags, Dandruff, Lymphomatoid Papulosis, SolarKeratosis, Mask of Pregnancy, Squamous Cell Carcinoma, Darier's Disease,Melanoma, Stasis Dermatitis, Dermatofibroma, Melasma, Sun Burn, DiaperDermatitis, Miliaria, Sun Damage, Discoid Lupus Erythematosus, Moles,Sun Spots, Dry Skin, Molluscum Contagiosum, Dyshidrotic Dermatitis,Mycosis Fungoides, Telogen Effluvium, Eczema, Atopic Myxoid Cysts, TineaCapitis, Dyshidrotic, Nail Splitting, Brittle, Tinea Corporis, NailFungus, Tinea Cruris, Necrobiosis Lipoidica Diabeticorum, Tinea Pedis,Nickel Allergy, Tinea Versicolor, Erythema Multiforme, NummularDermatitis, Urticaria, Erythema Nodosum, Onychomycosis, UrticariaPigmentosa, Folliculitis, Onychoschizia, Vitiligo, FolliculitisKeloidalis Nuchae, Perioral Dermatitis, Warts, Fordyce's Condition,Pfiesteria, Xanthomas, Granuloma Annulare, Pimples, Xerosis (Dry Skin),Pityriasis Alba, and yeast infection.

The foregoing description includes the best presently contemplated modeof carrying out the invention. This description is made for the purposeof illustrating the general principles of the inventions and should notbe taken in a limiting sense. This invention is further illustrated bythe following examples, which are not to be construed in any way asimposing limitations upon the scope thereof. On the contrary, it is tobe clearly understood that resort may be had to various otherembodiments, modifications, and equivalents thereof, which, afterreading the description herein, may suggest themselves to those skilledin the art without departing from the spirit of the present invention.

All terms used herein are considered to be interpreted in their normallyacceptable usage by those skilled in the art. Patents and patentapplications or references cited herein are all incorporated byreference in their entireties.

Example 1 Formation of a Matrix Including Acrylamide

A mixing tank was charged with 161.4 kg of water and 9.1894 kg ofacrylamide, 0.10347 kg of NNNN′-methylenebisacrylamide, and 9.3046 kg ofglycerol were added and mixed. Then 1.0213 kg of guar gum non-gellablepolysaccharide was dispersed in a mixture containing 0.9770 kg ofisopropyl alcohol and 2 kg of water. The solution of guar gum was thenadded and dispersed into the acrylamide mixture. After suitable mixing,0.1042 kg of TEMED was added and polymerization was catalyzed with0.0999 kg ammonium persulphate.

While the batch was still liquid, it was poured into molds to formsheets. After gelling had occurred, sheets were transferred to adessicator and dehydrated to form a stable intermediate stock sheet.Prior to cutting to size, the stock material was re-hydrated in a humidatmosphere. After cutting, the material was coated with petrolatum. Theresulting composition was then sealed into appropriate packaging andirradiated to sterilize it.

An embodiment of the invention is a hydrogel matrix composed of across-linked polyacrylamide scaffolding containing ingredients thatassist in the development and maintenance of an aqueous diffusiongradient in the nail plate. The matrix used in the prototypes utilizedthe formulation based on the Nangia patent (U.S. Pat. No. 5,196,390),such as that described above. The matrix was made by dissolving theacrylamide, bis acrylamide, guar gum, glycerol and citric acid in theaqueous charge and then initiated and catalyzed polymerization withTEMED and sodium persulfate. The resulting gel was cross linked hydrogelpolymer with aqueous moisture, glycerol and citric acid. Theconcentration of citric acid in the formulation was approximately 6 to16% w/w after the adjustment of the final water content to approximately50% by weight of the matrix using a dehumidifier.

Example 2

An alternative method for making a polyacrylamide matrix containingcitric acid as the active agent was performed. The steps of Example 1were followed, except the citric acid was not added. Once the matrix waspolymerized, it was formed into the desired shape, typically a sheetapproximately 25×25×0.5 cm in size. A sheet of hydrophilic matrix wascreated by dehydration at 45° C. resulting in approximately 3% w/wmoisture. The sheet was then reconstituted with the addition ofconcentrated solutions of citric acid to form sheets so that themoisture content was approximately 50% by weight. The concentration ofcitric acid in the prototypes was 6%, 8%, 10%, 12% and 16% by weight.

The polymerized matrices with these concentrations of acid retained thenormal properties of plain matrix material and were suitable forapplication. Sheets made by this procedure were sealed into medicalgrade polyethylene pouches until used.

Example 3

The application of the sheet to infected nails was carried out bycutting the matrix to the approximate size of the nail. This was thenplaced onto the nail and secured using a medical grade polyurethaneadhesive thin film dressing (OPSITE, Smith & Nephew). The cover dressingwas applied so that the matrix parts were completely boardered on allsizes. This prevented slippage of the matrix from the nail but alsooccluded air contact with the matrix which might lead to dehydration.Matrix applied in this fashion could be worn for up to one week buttypically were changed approximately every 2-3 days.

All prototypes, regardless of the concentration of citric acid wereeffective at hydrating the nail and particular the portion directly overactive fungal invasion (as apparent by the white discoloration of thenail). Several individuals that volunteered to wear samples of thevarious strengths complained of burning sensation when the 16% samplewas worn. This also occurred occasionally when the 12% sample was worn.However discontinuation resulted in relief of the sensation. Moreoverindividuals that experienced irritation with a higher concentrationcould all wear the 8% concentration without irritation.

After 1-2 applications, the portion of nail affected by fungi completelydetached from the nail bed and was free floating. This detached portioncould then be removed by scissors or clipper so that subsequentapplications of the invention were in direct contact with the nail bedwhere the fungi typically reside.

Typically nail bed areas took on nearly normal appearance after about 14days of application. Interestingly, the matrix has no apparent affect onhealthy nail so that there may be no disadvantage in prolongedapplication where there is a high risk of re-infection from thesurrounding area which often happens with people that have co-incidentathletes' foot infections.

Citric acid containing matrix was used in one case of an individual withaffected 7 toes (4 of the left foot and 3 on the right foot). Matrix wasregularly applied every other day for 21 days to the nails of the leftfoot. All of the nails were hydrated within the first application. Thedetached nail plate substrate over the areas infected were debrided andapplication continued. New nail growth was observed by the 10^(th) dayand continued until normal nail length was achieved. No changes wereobserved in the affected untreated nails of the right foot.

Example 4 Skin Sensitivity

Matrices were constructed with varying amounts of citric acid, glyceroland water, as described in Examples 1 or 2. These matrices were screenedfor irritation and sensitization by application to the skin surface ofvolunteers. The prototypes and exposure results are laid out in theTable 2. CA=citric acid.

TABLE 2 Skin irritation and sensitization reactions on human volunteers.Irritation Prototype Composition Reaction (+/−) A.1 Matrix containing 8%CA, 25% 0/5 glycerol and 25% water. A.2 Matrix containing 8% CA, 15% 0/5glycerol and 50% water A.3 Matrix containing 12% CA, 25% 1/7 glyceroland 25% water. A.4 Matrix containing 12% CA, 15% 0/5 glycerol and 50%water. A.5 Matrix containing 16% CA, 25% 3/5 glycerol and 25% water. A.6Matrix containing 16% CA, 15% 2/4 glycerol, and 50% water.The occurrence of undesirable reactions at the application sites wherematrices containing 16% citric acid caused the discontinuation ofinvestigation of materials containing this amount of acid.

Example 5 Inhibition of Fungal Growth

Antifungal activity was determined by growth inhibition using a modifiedzone inhibition type assay. Strains of fungi were propagated onSabouraud's Dextrose Agar until confluent. Aspergillus niger spores wereharvested by rinsing culture with saline containing Tween 20. Hyphalgrowth from dermatophytes was also harvested using saline containingTween 20. Hyphal growth was transferred to 15 ml sterile plastic tubeswith 10 ml Tween and 3-4 glass beads. The tubes were shaken for about2-3 minutes by hand to break up hyphae. Aliquots of 1.5 ml of hyphae orspore suspensions were dispensed to the surface of Sab-Hi agar medium(Sabouraud's containing Trypticase Soy Broth). The suspensions werespread evenly over the surface and then excess fluid was decanted anddiscarded. Samples of citric acid-containing, and control matrices asdescribed in Examples 1 and 2 were prepared by punch cutting using a 5mm bore punch. The samples were transferred to the plates and pressed toensure contact with the plates. The plates were then incubated at 30° C.in a humidified atmosphere for 3-5 days to allow fungal growth. Theplates were observed for overt appearance of zones of inhibition andthen microscopically under the specimens for mycelial invasion into thecontact area.

The specimens that were tested in the system were the control (FlexiGelHydrogel Wound Dressing (plain matrix)), matrix with 8% citric acid (50%hydrated) and matrix with 12% citric acid (again 50% hydrated). The testorganisms were Trichophyton rubrum, Epidermophyton, Microsporum, andAspergillus niger. The results are provided in Table 3.

TABLE 3 Prototype action on the growth of fungi on solid agar medium.[Diameter of Zone/Growth of fungi in contact area] Test OrganismFlexiGel Control Matrix 8% CA Matrix 12% CA Aspergillus niger 0 mm Heavy0 mm Heavy 0 mm Heavy Trichophyton 0 mm Heavy 5 mm None 9 mm NoneEpidermophyton 0 mm Heavy 2 mm None 4 mm None Microsporum 0 mm Heavy 9mm None 12 mm  NoneThese results showed that Aspergillus was not inhibited by either of thetest samples. Hyphae from this fungi grew up to, over, as well as underthe citric acid containing matrices. This is not surprising sinceAspergillus is commonly isolated from citrus fruits and in fact is usedcommercially to ferment cane sugar, molasses and dextrose into citricacid. The specimens containing citric acid inhibited all of the strainsof dermatophytes. The zones of inhibition were greatest withTrichophyton and Microsporum. Continued incubation of all of the plateseventually resulted in hyphal invasion of the inhibition zones of thedermatophytes. This was likely to be due to the equilibration of citricacid into the medium resulting in a decreased concentration in theimmediate vicinity of the test specimens. At the time of scanning (day 4post inoculation) no hyphae were detected under the CA containingsamples placed on the dermatophytes. By contrast, heavy hyphal growthwas present under the Control sample as well as under all specimenstested on Aspergillus.

Example 6 Transfer of Citric Acid Through Nail Plate

Effective inhibition of the dermatophytes responsible for nailinfections require the penetration of the citric acid to the junctionbetween the nail bed and the nail plate. A model of delivery was made bypreparing “artificial” nail plate from bovine hoof.

Preparation of bovine hoof: Beef hoof obtained from an abitor wascleaned with soap and water and then air dried. The hoof was thenmounted in a clamp device to secure it so that uniform shavings, whichwere small slabs of hoof, could be taken using a hand plane. Theshavings were taken parallel to the surface of the face of the hoof. Theshavings were collected and saved at 4° C. until required.

Transfer of acidity. The transfer of acidity from the prototypes wasevaluated by placing matrix with citric acid on top of a hoof shavingwhich was on top of a control matrix sample. In theory, the accumulationof acid in the control matrix would only result if it passed through thehoof. To confirm this, similar set-ups were made except that a layer ofpolyethylene sheet was also placed between the control and test matrixto confirm that passage “through” the hoof occurred. Acid accumulationwas shown by the measure of pH change, phenol red conversion, and citricacid detection (pyridine-acid anhydride test) after overnight incubationat room temperature. The results are in Table 4.

TABLE 4 Acid transfer through keratinized beef hoof simulation of nailplate. Sample Tested pH Phenol Red Pyridine FlexiGel Control 6.5  2 mmClear alone 12% Citric Acid 3.0 21 mm Dark Red alone FlexiGel below 4.010 mm Light yellow 12% CA FlexiGel below 6.0  2 mm Clear 12% CAseparated by poly filmThe results of this study showed that protons migrate readily throughthe hoof to the basal layer. The migration was not around the hoofshaving because it is blocked by a plastic impermeable barrier. Theamount of citrate that was delivered to the underlying substrate is lessthan the amount in the delivery substrate.

Example 7 Penetration of Acidity Through Human Nail Plate

A sample of nail clipping was taken from a volunteer as a control. Thevolunteer then applied the 12% CA matrix for overnight wear to a toe.The next day an additional clipping was taken from the treated toe nail.Both specimens were then oriented so that ventral aspect of eachclipping was situated against the surface of a phenol red agar plate.The plate was then incubated for 2 hours at room temperature todetermine if acidity penetrated through the nail plate. The untreatednail clipping showed no change in color of the surrounding phenol redwhereas the treated nail clipping had an area approximately one inch indiameter surrounding it with all red cleared, indicating acidification.This simple test showed that acidity penetrated rapidly through thehydration gradient created in the nail during the treatment.

The above studies showed that the agent and delivery method areeffective in the treatment of onychomycosis for the vast majority ofcases since dermatophytes cause as much as 96% of the cases.

Whereas this invention has been described in detail with particularreference to its most preferred embodiments, it is understood thatvariations and modifications can be effected within the spirit and scopeof the invention, as described herein before and as defined in theappended claims. The corresponding structures, materials, acts, andequivalents of all means plus function elements, if any, in the claimsbelow are intended to include any structure, material, or acts forperforming the functions in combination with other claimed elements asspecifically claimed.

1-17. (canceled)
 18. A composition for treatment of dermal structures, comprising, a) a cross-linked polyacrylamide matrix, a non-gellable polysaccharide, citric acid, and water.
 19. The composition of claim 18, wherein the citric acid is in a concentration of 8% to 16% w/w.
 20. The composition of claim 18, wherein the water content is from 0.1% to 50%.
 21. A method of treating a dermal condition comprising, a) applying to a dermal structure a composition comprising a hydrophilic polymer matrix, at least one active agent, and at least one humectant, wherein the composition has a moisture content ranging from about 0.1% to 50% to create a diffusion gradient from the composition to the dermal structure, wherein the hydrophilic polymer matrix directly contacts the dermal structure, wherein moisture and the at least one active agent are transferred by the diffusion gradient from the hydrophilic polymer matrix composition to the dermal structure; and b) maintaining the composition at the dermal structure site for a sufficient amount of time so that an effective amount of the active agent is delivered.
 22. The method of claim 21, wherein the dermal condition is an ungual condition and the dermal structure is an ungual structure.
 23. The method of claim 21, wherein the hydrophilic polymer matrix includes a cross-linked polyacrylamide.
 24. The method of claim 21, wherein the at least one active agent comprises an organic acid.
 25. The method of claim 24, wherein the organic acid comprises citric acid.
 26. The method of claim 25 wherein the citric acid is in a concentration between 0.1% w/w and 16% w/w.
 27. The method of claim 21 wherein the humectant includes glycerol.
 28. The method of claim 21, wherein the humectant is present at a concentration of from about 15% w/w to about 25% w/w.
 29. The method of claim 21, wherein the composition further comprises a moisture management system.
 30. The method of claim 29, wherein the moisture management system includes a non-gellable polysaccharide.
 31. The method of claim 31, wherein the non-gellable polysaccharide comprises guar gum, lucerne, fenugreek, honey locust bean gum, white clover bean gum, or carob locust bean gum.
 32. The method of claim 21, wherein the composition further comprises an attachment element.
 32. The method of claim 32, wherein the attachment element is an open pattern adhesive.
 33. The method of claim 33, wherein the open pattern adhesive comprises polysiloxane, a polyisobutylene, a polyacrylate, an acrylic acid-acrylate copolymer, a polyisobutene, a polybutadiene, a polystyrene-isoprene copolymer, a polystyrene-butadiene copolymer, a neoprene, a polyacrylic acid, a polymethacrylic acid, or a blend of a hydrophilic cellulose derivative with a polyethylene glycol. 